An activin/furin regulatory loop modulates the processing and secretion of inhibin alpha- and betaB-subunit dimers in pituitary gonadotrope cells

J Biol Chem. 2008 Nov 28;283(48):33059-68. doi: 10.1074/jbc.M804190200. Epub 2008 Sep 30.

Abstract

Of all ligands of the transforming growth factor beta superfamily, inhibins and activins are a physiologically relevant pair that are functional antagonists of each other. Activin stimulates whereas inhibin blocks follicle-stimulating hormone biosynthesis and secretion from pituitary gonadotrope cells, and together, inhibin and activin control the pituitary gonadal axis essential for normal reproductive function. Sharing a similar beta-subunit, the secretion of inhibin heterodimers (alpha/beta) or activin homodimers (beta/beta) as mature bioactive ligands depends, in part, on the proteolytic processing of precursor proteins. A short loop regulatory pathway controlling precursor processing and dimer secretion was discovered. Activin stimulates endogenous inhibin alpha- and betaB-subunit mRNA, protein, and proteolytic processing. Simultaneously, activin stimulated the proconvertase furin through a Smad2/3-dependent process. The data provide a mechanism where the regulation of furin and inhibin subunits cooperates in an important positive short feedback loop. This regulatory loop augments the secretion of bioactive mature activin B, as well as inhibin B dimers, necessary for local follicle-stimulating hormone beta regulation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Activins / metabolism*
  • Animals
  • Cell Line, Tumor
  • Dimerization
  • Follicle Stimulating Hormone / metabolism*
  • Furin / metabolism*
  • Gonadotrophs / cytology
  • Gonadotrophs / metabolism*
  • Humans
  • Inhibin-beta Subunits / metabolism*
  • Inhibins / metabolism*
  • Mice
  • RNA, Messenger / metabolism
  • Smad2 Protein / metabolism
  • Smad3 Protein / metabolism

Substances

  • INHBB protein, human
  • RNA, Messenger
  • SMAD2 protein, human
  • SMAD3 protein, human
  • Smad2 Protein
  • Smad3 Protein
  • inhibin-alpha subunit
  • Activins
  • Inhibins
  • Follicle Stimulating Hormone
  • Inhibin-beta Subunits
  • FURIN protein, human
  • Furin